N-hydroxyalkyl-2,4,6-triiodosuccinanilic acids

ABSTRACT

Compounds of the formula WHEREIN R1 is an alkyl group carrying at least one hydroxyl group and salts thereof with bases. The compounds are prepared by reacting 2,4,6-triiodosuccinanilic acid with a hydroxyalkylating agent. The compounds are useful as cholecystographic agents.

United States Patent Holtermann [451 May 30, 1972 [54]N-HYDROXYALKYL-2,4,6-

TRIIODOSUCCINANILIC ACIDS [72] Inventor: Hugo Holtermann, Baerum, Norway[73] Assignee: Nyegaard & Co. A/S, Oslo, Norway [22] Filed: June 6, 196921 Appl. No.: 831,207

[30] Foreign Application Priority Data June I1, 1968 Great Britain..27,698/68 [52] U.S. Cl ..260/519, 424/5 [51] Int. Cl ..C07c 103/32[58] Field of Search ..260/519 [56] References Cited OTHER PUBLICATIONSKarrer, Paul, Organic Chemistry 1950) Pub. by Elsevier Pub. Co., Inc.(New York) QD258K33c.5, page 453 Primary Examiner-Lorraine A. WeinbergerAssistant Examiner-L. Arnold Thaxton Attorney-Bacon & Thomas wherein Ris an alkyl group carrying at least one hydroxyl group and salts thereofwith bases. The compounds are prepared by reacting2,4,6-triiodosuccinanilic acid with a hydroxyalkylating agent. Thecompounds are useful as cholecystographic agents.

4 Claims, N0 Drawings N -HYDROXYALKYL-Z,4,6-TRIIODOSUCCINANILIC ACIDSThis invention concerns novel cholecystographic X-ray contrast agents.In the X-ray visualization of the gall bladder, it is desirable toadminister a contrast agent which will concentrate in the system to bevisualized, remain for a period sufficient for X- ray investigation andthen be excreted within a relatively short time. The contrast agentshould be non-toxic and free from undesirable side effects, such asnausea and diarrhoea and it is also particularly convenient if it can beadministered by the oral route.

Many cholecystographic agents have been proposed previously but haveshown poor absorption on oral administration, undue toxicity and sideeffects or disturbing shadows from the intestinal region. It has oftenbeen found that attempts to increase the rate of excretion have led tocompounds of increased toxicity.

We have now found that the N-hydroxyalkyl-2,4,6- triiodosuccinanilicacids have shown themselves to fulfill the desiderata of a goodcholecystographic agent particularly well and are in general superior tothe corresponding N-(unsubstituted alkyl)-compounds, in that they areless toxic while retaining approximately the same rate of bileexcretion.

According to the present invention we provide compounds of the generalFormula i COCHzCH2COOH I (wherein R an alkyl group carrying one or morehydroxyl groups) and their salts with bases.

R preferably possesses one to five carbon atoms and is mostadvantageously the hydroxyethyl or dihydroxypropyl group.

The new compounds according to the invention may be administered asacids or as salts. Salts for administration should, of course, byphysiologically acceptable at the doses normally employed in theparticular route of administration and such salts include, for example,alkali metal, e.g., sodium or potassium, salts or alkaline earth metal,e.g., calcium or magnesium, salts but other salts may be of use in theisolation of purification of the acids.

The new compounds according to the invention may be formulated foradministration in any convenient way, normally in conjunction with aradiological carrier or excipient. Although the oral formulations arethe most suitable in practice, the effective substances may beadministered by the rectal route where desirable, in appropriateformulations such as suppositories.

Oral formulations may, for example, take the form of tablets, coatedtablets, capsules, granulates, effervescent granulates and the like, thecarriers or excipients including for example, carriers such as a starch,sugar or talc; lubricants such as magnesium stearate; binding agentssuch as carboxymethyl cellulose; effervescent agents such as tartaricacid and sodium carbonate; oils; wetting agents; flavor agents and thelike.

A suitable dose for an adult will be in the range 2-6 grams of thecontrast substance. The formulations preferably take the form of dosageunits such as tablets, effervescent granulates or capsules, each ofwhich contains 0.25 to 3 g. Tablets containing 0.4 to 0.6 g are thepreferred dosage unit form.

The new compounds according to the invention can be prepared in anyconvenient way.

According to a further feature of the invention we provide a process forpreparing the new compounds of Formula I as defined above in which2,4,6-triiodosuccinanilic acid is reacted with a hydroxyalkylatingagent.

The hydroxyalkylating agent may, for example, be a ester, e.g., ahalide, sulphate or hydrocarbon-sulphonate of a hydroxyalkane;hydroxyalkyl groups can conveniently also be introduced by reaction withepoxides such as ethylene oxide or glycide. The hydroxyalkylationproceeds readily in aqueous media, under basic conditions, for examplein the presence of an alkali metal hydroxide, e.g., sodium or potassiumhydroxide; alcoholic media may also be used, under both neutral andbasic conditions, for example using an alkali metal alkoxide. Aqueousalcoholic media may also be used. Thus for example, suitable reagentsinclude ethylene oxide, glycide, 2- chloroethanol and3-chloro-propandiol-1,2. Halogenoalkyl esters such as B-chloroethylacetate may also be used, the ester grouping normally being hydrolyzedunder the reaction conditions.

The following examples are given by way of illustration only; infra redspectra were recorded on Perkin Elmer Model 21 Double Beam Spectrometerin KBr pellets. Melting points are not corrected. All temperatures arein C:

EXAMPLE 1 N-(B-Hydroxyethyl)-2,4,6Triiodosuccinanilic Acid Method A.B-Chloroethyl Acetate as Alkylating Agent 2,4,6Triiodosuccinanilic acid(11.4 g. 20 mmole) was suspended in methanol (120 ml) and partlydissolved by adding 4.9 M sodium methylate (16 ml, 79 mmole). B-Chloroethyl acetate (4.1 ml, 2 sq.) as added at room temperature andunder stirring. After 29 hours, 4.9M sodium methylate (8 ml) andB-chloroethyl acetate (4.1 ml) were added. After stirring for twenty onehours, the mixture was diluted with water (200 m1) and small amounts ofundissolved material filtered off. The product precipitated as whitecrystals by careful addition of 6N hydrochloric acid. Yield: 10.6 g (87percent). After two recrystallizations from ethyl acetate, the acidmelted at 152-166. (Found C 23.66; H 2.13; I 61.6; N 2.38; E 616. Calc.for C, H, l NO C 23.45; H 1.96; 1 61.9; N 2.28; E 615).

Method B. 2-Chloroethanol as Alkylating Agent. Sodium Methylate asSolvent.

2,4,6-Triiodosuccinanilic acid (5.7 g. 10 mmole) was suspended inmethanol (60 ml) and partly dissolved by adding 4.9M sodium methylate (8ml, 39 mmole). 2-Chloroethanol (1.35 ml, 2 equiv.) was added withstirring. After four and a half hours, 4.9M sodium methylate (4 ml) and2- chloroethanol (1.35 ml) were added. After stirring for the night, thelatter addition was repeated. After 4 hours, the reaction mixture wasdiluted with water ml), filtered and carefully acidified with 6Nhydrochloric acid. The reaction product precipitated as white crystals.Yield: 5.3 (87 percent). After two recrystallizations from ethylacetate,the acid melted at 152-l56. Its infrared spectrum was identical with thespectrum of the acid prepared by method A. (Found: C, 23.66; H, 2.01; I,60.7; N, 2.45. Calcd. for C, H, l NO,: C 23.45, H, 1.96; I, 61 .9; N,2.28).

Method C. 2-Chloroethanol as Alkylating Agent. A Mixture of Ethanol-5NSodium Hydroxide as Solvent. 2,4,6-Triiodosuccinanilic acid (5.7 g, 10mmole) was dissolved in a mixture of ethanol (15 ml) and 5N sodiumhydroxide (15 ml, 75 mmole) and heated at 60 (in the bath). Then2-chloroethanol (2.37 ml, 35 mmole) was added. After half an hour, thesolution was diluted with water (70 ml and acidified with 6Nhydrochloric acid. The product precipitated as a yellow oil, whichcrystallized over a few hours. Yield: 6 g. After two recrystallizationsfrom ethyl acetate, the product melted at 141-15 2. Its IR spectrum wasidentical with with spectra of the acids prepared by methods A and B.

EXAMPLE 2 N-(Dihydroxypropyl)-2,4,6-Triiodosuccinanilic Acid2,4,6-Triiodosuccinanilic acid (5.7 g; 0.01 mole) was suspended inmethanol (25 ml), and converted to its sodium salt by adding 4.6 Msodium methylate (2.35 ml; 0.01 mole). Glycide (1.9 ml; 0.03 mole) wasthen added and the mixture stirred for 4 days at room temperature. Afterfiltration, the filtrate was evaporated to dryness. The residue wasdissolved in water ml) and the free acid precipitated as a stickyproduct by adding 6N hydrochloric acid; Found I 55.8 Calculated for C HI NQ, I 59.1 On paper chromatography, eluting with butanol; ethanol;ammonia; water (4: 1:2: 1 the R, value was 0.38. The R, value of thestarting material was 0.59

The following examples of formulations are now given by way ofillustration only:

Formulation 1 Granulate 3 g of sodium salt ofN-(B-hydroxyethyl)-2,4,6-triiodo-succinanilic acid 4.8 g. offine sugar,0.05 g. of carboxymethyl cellulose 0.025 g. of polyhydroxymethylenestearate, 0.08 g. of flavoring The above substances are weighted out inthe above proportions moistened with alcohol and then granulated in thegranulating machine.

Formulation 2 Effervescent Granulate 3 g. sodium salt of N-(B,'y-dihydroxypropyl)-2,4,6-trii0dosuccinanilic acid 3.375 g. oftartaricacid, 0.0122 g. of polyhydroxy stearate, 0.0 l 22 g. of sodium laurylsulphonate, 3 g. of fine sugar, 2.25 g. sodium carbonate.

The above substances are weighted out in the above proportions moistenedwith alcohol and granulated.

Formulation 3 Tablets 0.75 kg. of maize starch are mixed with 5.00 kg.of sodium salt of N-(B-hydroxyethyl)-2,4,6-triiodosuccinanilic acid and0.75 kg. of sucrose.

The mixture is moistened with l ,000 cc. of 50 percent aqueous ethanoland then granulated in the machine, i.e., dried in a current of air at atemperature of 40 to 50 C. The dry granulate is screened, 0.70 kg. ofmaize starch. 0.05 kg. of talcum and 0.05 kg. of magnesium stearate areadded thereto and compressed to form 10,000 tablets.

Formulation 4 Capsules 05 g. of the sodium salt ofN-(B'y-dihydroxypropyl)-2,4.6- triiodosuccinanilic acid is filled intoone half of a gelatine cupsule and the other half of the capsule is thenfitted on top thereof. Both halves are then united and sealed to form agelatine capsule.

Formulation 5 Capsules 750 g. of sodium salt ofN-(B-hydroxyethyl)-2,4,6- triiodosuccinanilic acid 600 g. of sesame oil,and g of vegetable lecithin are stirred to form a paste and filled into1,000 gelatine capsules.

I claim: 1. A compound of the formula I cocmcmcoon

2. A compound as claimed in claim 1 in which R1 is selected from thegroup consisting of hydroxyethyl and dihydroxypropyl groups.
 3. Acompound as claimed in claim 1 in the form of a physiologicallyacceptable salt.
 4. A compound as claimed in claim 3 which is selectedfrom the group consisting of alkali metal and alkaline earth metalsalts.